An interaction between rifampicin and lamotrigine has been suspected on the basis of experimental data1 as well as case reports.2, 3 An investigation in ten healthy subjects pretreated with 600 mg rifampicin or placebo for 5 days and given a single dose of 25 mg lamotrigine showed a decrease in lamotrigine AUC of 44% and an increase in the apparent clearance of lamotrigine of 49%.1 The two case reports each focus on solitary patients treated with lamotrigine for epilepsy who experienced a reduction of lamotrigine serum concentrations after co‐treatment with either rifampicin, isoniazid, pyrazinamide, and ethambutol2 or rifampicin, isoniazid, and pyrazinamide3 for tuberculosis. In these reports, the magnitude of the rifampicin‐lamotrigine interaction may be obscured by an inhibitory effect of isoniazid on lamotrigine metabolism.2, 3 We report an interaction where a patient's lamotrigine therapy was monitored prior to, during, and after antimicrobial therapy with rifampicin and ciprofloxacin.
The patient was a 60‐year‐old male with a history of hypertension and bipolar disorder, for which he received nifedipine and lamotrigine, respectively. Lamotrigine had been administered at a regular dose of 200 mg twice daily for 3 years. Serum trough concentrations, monitored by an accredited liquid chromatography‐mass spectrometry method with an LOQ of 0.26 mg/L (1 μmol/L), were 6.4 and 7.7 mg/L (25 and 30 μmoles/L) 16 and 32 months prior to the event, respectively.
After a humerus fracture which was treated with marrow nailing, the patient developed an infection which required 4 months of oral therapy with rifampicin 450 mg twice daily and ciprofloxacin 750 mg twice daily. At the onset of antimicrobial therapy, nifedipine was substituted by valsartan (80 mg daily) because of an interaction between rifampicin and the former,4 whereas lamotrigine therapy was continued.
At subsequent follow‐up, the patient's mental status remained stable, while the lamotrigine serum concentration decreased compared to prior measurements. The patient denied any deviations from his regular lamotrigine dose schedule. A national interaction database administered by the Norwegian Medicinal Agency and accessed on the internet via The Norwegian Pharmaceutical Product Compendium (www.felleskatalogen.no) gave no information on any interactions between lamotrigine and rifampicin. The therapists then consulted a clinical pharmacologist who concluded that the observed reduction in the patient's serum concentration most likely was the result of an interaction with rifampicin and that a higher dose of lamotrigine should be considered for the duration of rifampicin administration. However, shortly thereafter, antimicrobial therapy was discontinued, with a subsequent return of serum lamotrigine concentrations to pre‐rifampicin/ciprofloxacin levels (Figure 1).
Figure 1.
Lamotrigine serum trough concentrations in a patient treated with a daily dose of 200 mg before, during, and after concomitant oral antimicrobial therapy with rifampicin 450 mg twice daily and ciprofloxacin 750 mg twice daily
Rifampicin is a potent inducer of several drug metabolising enzymes belonging to the cytochrome P450 superfamily and uridine 5′‐diphosphate glucuronosyl transferase system. It is not surprising that it may interact with lamotrigine, which is mainly eliminated by metabolic inactivation by the latter mechanism.1 However, there is a paucity of reports covering this interaction, and its magnitude and possible clinical impact has remained elusive. We assume that the observed interaction is caused by rifampicin alone acting on lamotrigine metabolism. Mean trough lamotrigine concentration on antimicrobial therapy (2.1 mg/L) divided by mean concentration off therapy (7.9 mg/L), but disregarding the concentration measured 2 weeks after cessation of antimicrobial therapy (3.1 mg/L) (Figure 1), implies that rifampicin induces a 73% reduction in serum steady state lamotrigine concentrations or, according to the equation Css = dose × bioavailability/dosing interval × Cltotal, a four times increase in apparent clearance. The discrepancy between previous experimental data1 and the present case may be due to higher drug doses and/or more extensive pretreatment with the inducer rifampicin in our case. Thus, the interaction between rifampicin and lamotrigine is extensive and of possible clinical significance.
COMPETING INTERESTS
There are no competing interests to declare. The patient has consented to publication.
Wimpelmann J, Høvik H, Riedel B, Slørdal L. The interaction between rifampicin and lamotrigine: A case report. Br J Clin Pharmacol. 2019;85:1859–1860. 10.1111/bcp.13973
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